Tetrahydropyridino or piperidino heterocyclic derivatives

ABSTRACT

A tetrahydropyridino or piperidino heterocyclic derivative represented by the formula [I]:
 
A-Het [I]
 
has a high affinity for CRF receptors and is effective against diseases in which CRF is considered to be involved.

This is a divisional of application Ser. No. 10/311,277 filed Aug. 25,2003, now U.S. Pat. No. 6,852,732 which is a National Stage ofPCT/JP01/05806, filed Jul. 4, 2001

TECHNICAL FIELD

The present invention relates to a therapeutic agent for diseases inwhich corticotropin releasing factor (CRF) is considered to be involved,such as depression, anxiety, Alzheimer's disease, Parkinson's disease,Huntington's chorea, eating disorder, hypertension, gastral diseases,drug dependence, cerebral infarction, cerebral ischemia, cerebral edema,cephalic external wound, inflammation, immunity-related diseases,alpecia, etc.

BACKGROUND ART

CRF is a hormone comprising 41 amino acids (Science, 213, 1394–1397,1981; and J. Neurosci., 7, 88–100, 1987), and it is suggested that CRFplays a core role in biological reactions against stresses (Cell. Mol.Neurobiol., 14, 579–588, 1994; Endocrinol., 132, 723–728, 1994; andNeuroendocrinol. 61, 445–452, 1995). For CRF, there are the followingtwo paths: a path by which CRF acts on peripheral immune system orsympathetic nervous system through hypothalamus-pituitary-adrenalsystem, and a path by which CRF functions as a neurotransmitter incentral nervous system (in Corticotropin Releasing Factor: Basic andClinical Studies of a Neuropeptide, pp. 29–52, 1990). Intraventricularadministration of CRF to hypophy-sectomized rats and normal rats causesan anxiety-like symptom in both types of rats (Pharmacol. Rev., 43,425–473, 1991; and Brain Res. Rev., 15, 71–100, 1990). That is, thereare suggested the participation of CRF in hypothalamus-pituitary-adrenalsystem and the pathway by which CRF functions as a neurotransmitter incentral nervous system.

The review by Owens and Nemeroff in 1991 summarizes diseases in whichCRF is involved (Pharmacol. Rev., 43, 425–474, 1991). That is, CRF isinvolved in depression, anxiety, Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, eating disorder, hypertension, gastraldiseases, drug dependence, inflammation, immunity-related diseases, etc.It has recently been reported that CRF is involved also in epilepsy,cerebral infarction, cerebral ischemia, cerebral edema, and cephalicexternal wound (Brain Res. 545, 339–342, 1991; Ann. Neurol. 31, 48–498,1992; Dev. Brain Res. 91, 245–251, 1996; and Brain Res. 744, 166–170,1997). Accordingly, antagonists against CRF receptors are useful astherapeutic agents for the diseases described above.

An object of the present invention is to provide an antagonist againstCRF receptors which is effective as a therapeutic or prophylactic agentfor diseases in which CRF is considered to be involved, such asdepression, anxiety, Alzheimer's disease, Parkinson's disease,Huntington's chorea, eating disorder, hypertension, gastral diseases,drug dependence, epilepsy, cerebral infarction, cerebral ischemia,cerebral edema, cephalic external wound, inflammation, immunity-relateddiseases, alpecia, etc.

DISCLOSURE OF THE INVENTION

The present inventors earnestly investigated tetrahydropyridino orpiperidino heterocyclic derivatives and consequently found noveltetrahydropyridino or piperidino heterocyclic derivatives having a highaffinity for CRF receptors, whereby the present invention has beenaccomplished.

The present invention is explained below.

The present invention is a tetrahydropyridino or piperidino heterocyclicderivative represented by the following formula [I]:A-Het   [I]wherein A is a group represented by the following formula [II] or [III]:

wherein the position of substitution by the Y—(CH₂)_(n)-group of thegroup represented by the formula [II] is 4-position or 5-position, theposition of substitution by the Y—C(R⁰)═ group of the group representedby the formula [III] is 3-position or 4-position,

R⁰ is a hydrogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl group or aC₃₋₈cycloalkyl-C₁₋₅alkyl group,

n is an integer of 0 to 5, and

Y is a cyano group, a group represented by the formula —CONR¹(R²)(wherein each of R¹ and R², which may be the same or different, is ahydrogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl group, aC₃₋₈cycloalkyl-C₁₋₅alkyl group, a C₁₋₅alkoxy-C₁₋₅alkyl group, aC₃₋₈cyclo-alkyloxy-C₁₋₅alkyl group or a phenyl group, or R¹ and R², whentaken together with the adjacent nitrogen atom, represent a 5- to8-membered saturated heterocyclic group represented by the formula:

(wherein B is CH₂, NH, N—C₁₋₅alkyl, N—C₃₋₈cycloalkyl,N—C₁₋₅alkyl-C₃₋₈cycloalkyl, O or S)) or a group represented by theformula —CO₂R³ (wherein R³ is a hydrogen atom, a C₁₋₅alkyl group, aC₃₋₈cycloalkyl group, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, aC₁₋₅alkoxy-C₁₋₅alkyl group, a C₃₋₈cycloalkyloxy-C₁₋₅alkyl group or aphenyl group), and

Het is any of heterocyclic groups represented by the following formulasform(01) to form(20):

wherein E is CH or N,

R⁴ is a hydrogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl group, aC₃₋₈cycloalkyl-C₁₋₅alkyl group, a hydroxyl group, a C₁₋₅alkoxy group, aC₃₋₈cycloalkyloxy group, or a group represented by the formula—N(R¹⁰)R¹¹ (wherein each of R¹⁰ and R¹¹, which may be the same ordifferent, is a hydrogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl groupor a C₃₋₈cycloalkyl-C₁₋₅alkyl group),

each of R⁵, R⁶, R⁷ and R⁸, which may be the same or different, is ahydrogen atom, a halogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkylgroup, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, a hydroxyl group, a C₁₋₅alkoxygroup, a C₃₋₈cycloalkyloxy group, a group represented by the formula—N(R¹²)R¹³ (wherein each of R¹² and R¹³, which may be the same ordifferent, is a hydrogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl groupor a C₃₋₈cycloalkyl-C₁₋₅alkyl group), a group represented by the formula—CO₂R¹⁴ (wherein R¹⁴ is a hydrogen atom, a C₁₋₅alkyl group, aC₃₋₈cycloalkyl group, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, aC₁₋₅alkoxy-C₁₋₅alkyl group, a C₃₋₈cycloalkyloxy-C₁₋₅alkyl group or aphenyl group), a cyano group, a nitro group, a C₁₋₅alkylthio group, atrifluoromethyl group or a trifluoromethoxy group,

R⁹ is a hydrogen atom, a C₁₋₅alkyl group, a C₂₋₅alkenyl group, aC₂₋₅alkynyl group, a C₃₋₈cycloalkyl group or a C₃₋₈cycloalkyl-C₁₋₅alkylgroup, and

Ar is an aryl or heteroaryl group unsubstituted or substituted with 1 to3 substituents which may be the same or different and are selected fromhalogen atoms, C₁₋₅alkyl groups, C₁₋₅alkoxy groups, C₁₋₅alkylthiogroups, trifluoromethyl group, trifluoromethoxy group and groupsrepresented by the formula —N(R¹⁵)R¹⁶ (wherein each of R¹⁵ and R¹⁶,which may be the same or different, is a hydrogen atom or a C₁₋₅alkylgroup); or a pharmaceutically acceptable salt thereof or its hydrate.

The terms used in the present specification have the following meanings.

The term “C₁₋₅alkyl group” means a straight chain or branched chainalkyl group of 1 to 5 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl or the like. Theterm “C₂₋₅alkenyl group” means a straight chain or branched chainalkenyl group of 2 to 5 carbon atoms, such as vinyl, 1-propenyl,2-propenyl, 1-methylvinyl or the like. The term “C₂₋₅alkynyl group”means a straight chain or branched chain alkynyl group of 2 to 5 carbonatoms, such as ethynyl, 2-propynyl or the like. The term “C₃₋₈cycloalkylgroup” means a cyclic alkyl group of 3 to 8 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or thelike. The term “C₃₋₈cycloalkyl-C₁₋₅alkyl group” means a substitutedC₁₋₅alkyl group having the above-mentioned C₃₋₈cycloalkyl group as thesubstituent, such as cyclopropylmethyl, cyclopropylethyl,cyclopentylethyl or the like.

For B, the term “N—C₁₋₅alkyl” means a group having a C₁₋₅alkyl group asa substituent on the nitrogen atom. The term “N—C₃₋₈cycloalkyl” means agroup having a C₃₋₈cycloalkyl group as a substituent on the nitrogenatom. The term “N—C₁₋₅alkyl-C₃₋₈cycloalkyl” means a group having aC₃₋₈cycloalkyl-C₁₋₅alkyl group as a substituent on the nitrogen atom.

The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom or an iodine atom. The term “C₁₋₅alkoxy group” means astraight chain or branched chain alkoxy group of 1 to 5 carbon atoms,such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy,pentyloxy, isopentyloxy or the like. The term “C₃₋₈cycloalkyloxy group”means a cyclic alkoxy group of 3 to 8 carbon atoms, such ascyclopropyloxy, cyclobutyloxy, cyclopentyloxy or the like. The term“C₁₋₅alkoxy-C₁₋₅alkyl group”means a substituted C₁₋₅alkyl group having aC₁₋₅alkoxy group as the substituent, such as methoxymethyl,2-ethoxyethyl or the like. The term “C₃₋₈cycloalkyloxy-C₁₋₅alkyl group”means a substituted C₁₋₅alkyl group having a C₃₋₈cycloalkoxy group asthe substituent, such as cyclopropyloxymethyl, 2-cyclopropyloxyethyl orthe like. The term “C₁₋₅alkylthio group” means a straight chain orbranched chain alkylthio group of 1 to 5 carbon atoms, such asmethylthio, ethylthio, propylthio or the like.

The term “aryl group” means a phenyl group, a naphthyl group or thelike. The term “heteroaryl group” means a heterocyclic group having inits ring 1 to 4 atoms which may be the same or different and areselected from nitrogen, oxygen and sulfur, such as pyridyl, quinolyl,indolyl, benzofuranyl, benzothiadiazolyl, benzofurazanyl, quinoxalinylor the like. Therefore, the substituted aryl or heteroaryl groupincludes, for example, 2,4,6-trimethylphenyl group, 2,4,6-tribromophenylgroup, 2,4-dibromo-6-chlorophenyl group, 2,4-dichlorophenyl group,2,4,6-trichlorophenyl group, 2-methyl-4-methoxyphenyl group,2,4-dibromo-6-fluorophenyl group, 2,4-dibromo-6-methylphenyl group,2,4-dibromo-6-methoxyphenyl group, 2,4-dibromo-6-methylthiophenyl group,2,6-dibromo-4-isopropylphenyl group, 2,6-dibromo-4-trifluoromethylphenylgroup, 2-chloro-4-trifluoromethylphenyl group,2-chloro-4-trifluoromethoxyphenyl group,6-dimethylamino-4-methylpyridin-3-yl group,2-chloro-6-trifluoromethylpyridin-3-yl group,2-chloro-6-trifluoromethoxypyridin-3-yl group,2-chloro-6-methoxypyridin-3-yl group,2-trifluoromethyl-6-methoxypyridin-3-yl group,2-chloro-6-difluoromethylpyridin-3-yl group, 2-methyl-6-methoxypyridin3-yl group, 2,6-dimethoxypyridin-3-yl group,5,7-dimethyl-2,1,3-benzothiadiazol-4-yl group,5,7-dimethylbenzofurazan-4-yl group, 6,8-dimethylquinoxalin-5-yl group,5,7-dichloro-2,1,3-benzothiadiazol-4-yl, 5,7-dichlorobenzofurazan-4-ylgroup and 6,8-dichloroquinoxalin-5-yl group.

The pharmaceutically acceptable salt in the present invention includes,for example, salts with an inorganic acid such as sulfuric acid,hydrochloric acid, phosphoric acid or the like; salts with an organicacid such as acetic acid, oxalic acid, lactic acid, tartaric acid,fumaric acid, maleic acid, citric acid, benzenesulfonic acid,methanesulfonic acid, p-toluenesulfonic acid or the like; and salts witha metal ion such as lithium ion, sodium ion, potassium ion, calcium ion,magnesium ion, zinc ion or the like.

Preferable examples of the compound of the present invention are asfollows.

That is, preferable are compounds of the formula [I] in which A is agroup represented by the formula [II]. More preferable are compounds ofthe formula [I] in which A is a group represented by the formula [II], Yis a carbamoyl group and n is 0 or 1. In addition, preferable arecompounds of the formula [I] in which Het is a heterocyclic grouprepresented by form(01) or form(12). More preferable are compounds ofthe formula [I] in which Het is a heterocyclic group represented byform(01) or form(12), and Ar is a phenyl group having two or threesubstituents which may be the same or different and are selected fromhalogen atoms, C₁₋₅alkyl groups, C₁₋₅alkoxy groups, C₁₋₅alkylthiogroups, trifluoromethyl group and trifluoromethoxy group. Still morepreferable are compounds of the formula [I] in which Het is aheterocyclic group represented by form(01) or form(12), and Ar is aphenyl group having two or three substituents which may be the same ordifferent and are selected from chlorine atom, trifluoromethyl group andtrifluoromethoxy group.

The compound of the formula [I] can be produced, for example, by any ofthe processes shown in the following reaction schemes 1 to 7 (in thefollowing reaction schemes, A, Het, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are asdefined above, R¹⁷ is a C₁₋₅alkyl group or a phenyl group, and X⁴ is achlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxygroup, a benzene-sulfonyloxy group, a toluenesulfonyloxy group or atrifluoromethanesulfonyloxy group).

Step 1:

Compound (2) can be obtained by halogenation or sulfonylation of thehydroxyl group of Compound (1). Here, the halogenation refers toreaction with a halogenating reagent such as phosphorus oxychloride,phosphorus pentachloride, sulfuryl chloride, thionyl chloride, thionylbromide, oxalyl chloride or the like in the presence or absence of, forexample, N,N-dimethylaniline or N,N-diethylaniline without a solvent orin an inert solvent such as a hydrocarbon (e.g., benzene and toluene) ora halogen-containing solvent (e.g., chloroform and dichloromethane). Thesulfonylation refers to reaction with a sulfonylating reagent such asmethanesulfonyl chloride, p-toluenesulfonyl chloride,trifluoromethanesulfonic acid anhydride, N-chloridephenylbis(trifluoromethanesulfonimide) or the like in the presence orabsence of a base in an inert solvent such as an ether (e.g., diethylether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane), ahydrocarbon (e.g., benzene and toluene), an amide (e.g.,N,N-dimethylformamide and N-methylpyrrolidone), acetonitrile, dimethylsulfoxide, pyridine, or a mixture of solvents selected from these inertsolvents. Here, the base includes, for example, organic bases such astriethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]-7-undecene and the like; and inorganic basessuch as sodium hydride, potassium hydride, sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate, sodium amide and the like.

Step 2:

Compound (3), the compound of the present invention, can be obtained byreacting Compound (2) with Compound (4) in an inert solvent in thepresence or absence of a base. Here, the base includes, for example,amines such as triethylamine, diisopropylethylamine, pyridine and thelike; inorganic bases such as sodium carbonate, potassium carbonate,sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide,barium hydroxide, sodium hydride and the like; metal alcoholates such assodium methoxide, sodium ethoxide, potassium tert-butoxide and the like;metal amides such as sodium amide, lithium diisopropylamide and thelike; and Grignard reagents such as methylmagnesium bromide and thelike. The inert solvent includes, for example, alcohols such asmethanol, ethanol, isopropyl alcohol, ethylene glycol and the like;ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane and the like; hydrocarbons such as benzene, tolueneand the like; amides such as N,N-dimethylformamide, N-methylpyrrolidoneand the like; acetonitrile; dimethyl sulfoxide; pyridine; water; andmixtures of solvents selected from these inert solvents.

Compound (9) of the present invention can be synthesized according alsoto the following reaction scheme 2.

Step 3:

Compound (6) can be obtained by reacting Compound (2) with Compound (5)in an inert solvent in the presence or absence of a base. Here, the baseincludes, for example, amines such as triethylamine,diisopropylethylamine, pyridine and the like; inorganic bases such assodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate, sodium hydroxide, barium hydroxide, sodiumhydride and the like; metal alcoholates such as sodium methoxide, sodiumethoxide, potassium tert-butoxide and the like; metal amides such assodium amide, lithium diisopropylamide and the like; and Grignardreagents such as methylmagnesium bromide and the like. The inert solventincludes, for example, alcohols such as methanol, ethanol, isopropylalcohol, ethylene glycol and the like; ethers such as diethyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like;hydrocarbons such as benzene, toluene and the like; amides such asN,N-dimethylformamide, N-methylpyrrolidone and the like; acetonitrile;dimethyl sulfoxide; pyridine; water; and mixtures of solvents selectedfrom these inert solvents.

Step 4:

Compound (6) can be converted to Compound (7) by removing the acetalprotective group of Compound (6) by conventional hydrolysis under acidicconditions (see Theodora W. Greene and Peter G. W. Wuts “ProtectiveGroups in Organic Synthesis”).

Step 5:

Compound (7) can be converted to Compound (8) by reacting Compound (7)in the presence of a cyanating agent such as sodium cyanide, potassiumcyanide, trimethylsilyl cyanide or the like in an inert solvent such asan alcohol (e.g., methanol, ethanol, isopropyl alcohol and ethyleneglycol), an ether (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane), acetonitrile, acetic acid, water, or a mixture ofsolvents selected from these inert solvents; and then reacting thecyanation product with, for example, phosphorus oxychloride, thionylchloride, methanesulfonyl chloride, p-toluenesulfonyl chloride ortrifluoroacetic anhydride in the presence or absence of an organic basesuch as pyridine, triethylamine or diisopropylethylamine in an inertsolvent such as a halogen-containing solvent (e.g., dichloromethane andchloroform), an ether (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxaneand 1,2-dimethoxyethane), a hydrocarbon (e.g., benzene and toluene) orthe like.

Step 6:

Compound (8) can be converted to Compound (9) of the present inventionby reacting the cyano group of Compound (8) by using, for example,sulfuric acid, hydrogen chloride and formic acid singly or incombination of two or more thereof, in an inert solvent such as ahalogen-containing solvent (e.g., dichloromethane and chloroform), anether (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane), a hydrocarbon (e.g., benzene and toluene), wateror a mixture of solvents selected from these inert solvents.

In addition, Compound (10) and Compound (17) of the present inventioncan be obtained according also to the following reaction scheme 3.

Step 7:

Compound (7) can be converted to Compound (13) by reacting Compound (7)with either Compound (11) or Compound (12) in an inert solvent in thepresence or absence of a base. Here, the base includes, for example,sodium hydride, potassium hydride, sodium methoxide, potassiumtert-butoxide, n-butyllithium, lithium bis(trimethylsilyl)amide, sodiumamide and potassium carbonate. If necessary, 18-crown-6 ether,15-crown-5 ether, tetramethylethylenediamine, hexamethylphosphoramideand the like can be used as an additive. The inert solvent includes, forexample, ethers such as diethyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like; hydrocarbons such as benzene, tolueneand the like; alcohols such as ethanol, methanol and the like; amidessuch as N,N-dimethylformamide, N-methylpyrrolidone and the like;tetramethylurea; dimethyl sulfoxide; water; and mixtures of solventsselected from these inert solvents.

Step 8:

When R³ of Compound (13) is a group other than a hydrogen atom, Compound(13) can be converted to Compound (14) of the present invention byconventional hydrolysis of the ester portion under acidic or basicconditions (see Theodora W. Greene and Peter G. W. Wuts “ProtectiveGroups in Organic Synthesis”).

Step 9:

Compound (10) of the present invention can be obtained by amidation ofCompound (14). Here, the amidation refers to general amidation of thecarboxyl group, and refers to any of the following reactions: thereaction of Compound (15) with a mixed acid anhydride obtained by thereaction of Compound (14) with a haloformic acid ester (e.g., ethylchloroformate and isobutyl chloroformate) or an acid halide (e.g.,benzoyl chloride and pivaloyl chloride) in the presence of a base suchas N-methylmorpholine, triethylamine or the like; the reaction ofCompound (14) with Compound (15) in the presence of a condensing agentsuch as N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), carbonyldiimidazole(CDI), diphenylphosphorylazide (DPPA), diethyl cyanophosphate or thelike and optionally an additive such as 1-hydroxybenzotriazole (HOBt),N-hydroxysuccinimide, 4-dimethylaminopyridine or the like; and thereaction of Compound (15) with an acid halide obtained by the reactionof Compound (14) with a halogenating reagent such as thionyl chloride,oxalyl chloride, carbon tetrabromide-triphenylphosphine or the like.

Step 10:

Compound (13) can be converted to Compound (16) by reacting Compound(13) in the presence of an acid or a base in an inert solvent. Here, theacid includes, for example, inorganic acids such as hydrogen chloride,hydrobromic acid, sulfuric acid and the like; and organic acids such asacetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like.The base includes inorganic bases such as sodium hydroxide, potassiumhydroxide, potassium carbonate and the like. The inert solvent includes,for example, ethers such as diethyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like; hydrocarbons such as benzene, tolueneand the like; alcohols such as ethanol, methanol and the like; amidessuch as N,N-dimethylformamide, N-methylpyrrolidone and the like;tetramethylurea; dimethyl sulfoxide; water; acetone; and mixtures ofsolvents selected from these inert solvents. When R³ is a group otherthan a hydrogen atom, employment of a solvent for reaction composed ofwater alone or a mixture of water and one or more other solvents makesit possible to carry out the conversion of R³ to a hydrogen atom and theconversion of Compound (13) to Compound (16) simultaneously.

Step 11:

When R³ is a group other than a hydrogen atom, R³ is converted to ahydrogen atom by the same procedure as in Step 8, after which Compound(17) of the present invention can be obtained by the same reaction as inStep 9.

Compounds (22), (23) and (24) can be synthesized according also to thefollowing reaction scheme 4.

Step 12:

Compound (20) can be obtained by reacting Compound (18) with Compound(19) in an inert solvent in the presence of a base. Here, the inertsolvent includes, for example, ethers such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane and the like; hydrocarbons such asbenzene, toluene and the like; alcohols such as ethanol, methanol andthe like; amides such as N,N-dimethylformamide, N-methylpyrrolidone andthe like; tetramethylurea; dimethyl sulfoxide; and mixtures of solventsselected from these inert solvents. The base includes, for example,amines such as triethylamine, diisopropylethylamine, pyridine and thelike; inorganic bases such as sodium hydride, potassium hydride, sodiumcarbonate and the like; metal alcoholates such as sodium methoxide,sodium ethoxide, potassium tert-butoxide and the like; alkyl metals suchas n-butyllithium, tert-butyllithium, phenyllithium and the like; andmetal amides such as lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, sodium amide and the like.

Step 13:

Compound (20) can be converted to Compound (21) by reduction of theketone portion represented by hydride reduction using sodium boronhydride, and hydrogenation (see Ahmed F. Abdel-Magid “Reductions inOrganic Synthesis”).

Step 14:

Compound (21) can be converted to Compound (22) by reacting Compound(21) with, for example, phosphorus oxychloride, thionyl chloride,methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoroaceticanhydride in the presence or absence of an organic base such aspyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine,1,8-diazabicyclo [5.4.0]-7-undecene or the like in an inert solvent suchas a halogen-containing solvent (e.g., dichloromethane and chloroform),an ether (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane), a hydrocarbon (e.g., benzene and toluene) or thelike, or by reacting Compound (21) with, for example, sulfuric acid,trifluoroacetic acid or formic acid in an inert solvent such as ahalogen-containing solvent (e.g., dichloromethane and chloroform), anether (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane), a hydrocarbon (e.g., benzene and toluene) or thelike.

Step 15:

Compound (22) can be converted to Compound (23) of the present inventionby converting the ester portion of Compound (22) to a carboxyl group bythe same procedure as in Step 8.

Step 16:

Compound (23) can be converted to Compound (24) of the present inventionby reacting Compound (23) with Compound (15) by the same procedure as inStep 9.

Compound (29) of the present invention can be synthesized according alsoto the following reaction scheme 5.

Step 17:

Compound (26) can be obtained by halogenating or sulfonylating thehydroxyl group of Compound (25) by the same procedure as in Step 1, andthen reacting the halogenation or sulfonylation product with Compound(5) in an inert solvent in the presence or absence of a base. Here, thebase includes, for example, organic bases such as triethylamine,diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene andthe like; and inorganic bases such as sodium hydride, potassium hydride,sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodiumamide and the like. The inert solvent includes, for example, ethers suchas diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andthe like; hydrocarbons such as benzene, toluene and the like; amidessuch as N,N-dimethylformamide, N-methylpyrrolidone and the like;acetonitrile; dimethyl sulfoxide; pyridine; and mixtures of solventsselected from these inert solvents.

Step 18:

Compound (26) can be converted to Compound (28) by reacting Compound(26) with an aryl-boric acid derivative (27) in an inert solvent in thepresence of a base, a zero-valence palladium complex (e.g.,tetrakis(triphenylphosphine)palladium andtetrakis(tributylphosphine)palladium) or a divalent palladium complex(e.g., palladium acetate and palladium chloride) and optionally aphosphine (e.g., triphenylphosphine and tributylphosphine). Here, thebase includes, for example, inorganic bases such as sodium carbonate,sodium hydrogencarbonate, potassium carbonate, barium hydroxide, sodiumhydroxide and the like; and organic bases such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like.The inert solvent includes, for example, halogen-containing solventssuch as dichloromethane, chloroform and the like; ethers such as diethylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like;hydrocarbons such as benzene, toluene and the like; alcohols such asmethanol, ethanol and the like; water; and mixtures of solvents selectedfrom these inert solvents.

Step 19, Step 20 and Step 21:

Compound (29) of the present invention can be obtained by carrying outStep 19, Step 20 and Step 21 in the same manner as for Step 4, Step 5and Step 6, respectively.

Compound (32) of the present invention can be synthesized according alsoto the following reaction scheme 6.

Step 22:

Compound (31) can be obtained by halogenating or sulfonylating thehydroxyl group of Compound (25) by the same procedure as in Step 1, andthen reacting the halogenation or sulfonylation product with Compound(4) in an inert solvent in the presence or absence of a base. Here, thebase includes, for example, organic bases such as triethylamine,diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene andthe like; and inorganic bases such as sodium hydride, potassium hydride,sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodiumamide and the like. The inert solvent includes, for example, ethers suchas diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane andthe like; hydrocarbons such as benzene, toluene and the like; amidessuch as N,N-dimethylformamide, N-methylpyrrolidone and the like;acetonitrile; dimethyl sulfoxide; pyridine; and mixtures of solventsselected from these inert solvents.

Step 23:

Compound (32) of the present invention can be obtained by the sameprocedure as in Step 18.

Compounds (33), (34) and (35) of the present invention can besynthesized according also to the following reaction scheme 7.

Step 24:

Compounds (33) and (34) of the present invention can be converted toeach other by conventional protection and deprotection of the esterportion and the carboxylic acid portion (see Theodora W. Greene andPeter G. W. Wuts “Protective Groups in Organic Synthesis”).

Step 25:

Compound (34) of the present invention can be converted to Compound (35)of the present invention by conventional amidation in the same manner asin Step 9. Compound (35) can be converted to Compound (34) by convertingthe amide portion of Compound (35) to a carboxylic acid by conventionalhydrolysis (see Theodora W. Greene and Peter G. W. Wuts “ProtectiveGroups in Organic Synthesis”).

The compound of the present invention is useful as a therapeutic orprophylactic agent for diseases in which CRF is considered to beinvolved. For this purpose, the compound of the present invention can beformulated into tablets, pills, capsules, granules, powders, solutions,emulsions, suspensions, injections and the like by a conventionalpreparation technique by adding conventional fillers, binders,disintegrators, pH-adjusting agents, solvents, etc.

The compound of the present invention can be administered to an adultpatient in a dose of 0.1 to 500 mg per day in one portion or severalportions orally or parenterally. The dose can be properly increased ordecreased depending on the kind of a disease and the age, body weightand symptom of a patient.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is concretely explained with reference to thefollowing examples and test example, but is not limited thereto.

EXAMPLE 1 Synthesis of8-(2,4-dichlorophenyl)-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline(compound 1-01)

After 60% sodium hydride (an oil dispersion) (79 mg) was washed withhexane and then suspended in N,N-dimethylformamide (3 mL), thesuspension was cooled with ice. To the cooled suspension was added8-(2,4-dichlorophenyl)-2-methyl-4-hydroxyquinoline (500 mg) all at once,and the resulting mixture was stirred under ice-cooling for 10 minutesand then at room temperature for another 30 minutes. To the solutionthus obtained was added N-phenylbis(trifluoromethanesulfonimide) (703mg) all at once, and the resulting mixture was stirred at roomtemperature for 30 minutes.

To the resultant reaction mixture were added sodium hydrogencarbonate(413 mg) and 4-carbamoyl-1,2,3,6-tetrahydropyridine hydrochloride (533mg), and the resulting mixture was vigorously stirred at 120° C. for 1hour.

The reaction mixture thus obtained was cooled to room temperature andthen separated with chloroform and water. The aqueous layer wasextracted with chloroform and the combined organic layer was dried overanhydrous sodium sulfate, after which the desiccating agent was filteredoff and the filtrate was concentrated under reduced pressure. Theresidue was purified by a silica gel column chromatography (silica gel:Wako Gel (C200), eluent: chloroform-methanol=10:1), and the crystalsthus obtained were washed with methanol and then tetrahydrofuran toobtain the title compound (156 mg).

m.p. 263.5–265.5° C.

Table 1, Table 2, Table 7, Table 17 and Table 18 list the compoundobtained in Example 1 and compounds obtained by the same procedure as inExample 1.

EXAMPLE 2 Synthesis of8-(2,4-dichlorophenyl)-4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2methylquinoline(compound 1-15)

(1) In phosphorus oxychloride (5 mL),8-(2,4-dichloropheny1)-2methyl-4-hydroxyquinoline (2.0 g) was heatedunder reflux for 1 hour. The reaction mixture was cooled to roomtemperature and carefully poured into ice water, and the resultingmixture was separated with a saturated aqueous sodium hydrogencarbonatesolution and ethyl acetate. The organic layer was dried over anhydroussodium sulfate, after which the desiccating agent was filtered off andthe filtrate was concentrated under reduced pressure to obtain a solid(2.1 g).

(2) A mixture of the solid (200 mg) obtained in (1),5-carbamoyl-1,2,3,6-tetrahydropyridine hydrochloride (121 mg),diisopropylethylamine (240 mg) and ethanol (1 mL)-water (0.075 mL) wasallowed to react in a sealed tube at 80° C. for 10 days. The reactionmixture was cooled to room temperature, poured into a saturated aqueoussodium hydrogencarbonate solution, and then extracted three times withchloroform. The combined organic layer was dried over anhydrous sodiumsulfate, after which the desiccating agent was filtered off and thefiltrate was concentrated under reduced pressure. The residue waspurified by a silica gel column chromatography (silica gel: Wako Gel(C200), eluent: chloroform-methanol=10:1) and then crystallized fromethyl acetate to obtain the title compound (159 mg).

m.p. 230.0–232.0° C.

Table 1, Table 2, Tables 3 to 11, Table 13, Table 16, Table 19 and Table20 list the compound obtained in Example 2 and compounds obtained by thesame procedure as in Example 2.

EXAMPLE 3 Synthesis of8-(2,4-dichlorophenyl)-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline(compound 1-01)

(1) In N,N-dimethylformamide (50 mL),4-chloro-8-(2,4-dichloropheny1)-2-methylquinoline (3.3 g) obtained bythe same procedure as in Example 2, (1) and 4-piperidone ethylene ketal(7.5 g) were stirred at 120° C. for 2 hours and then at 150°0 C. for 2hours, and the resulting mixture was heated under reflux for 3.5 hours.The solvent was distilled off under reduced pressure, after which waterand a saturated aqueous sodium hydrogencarbonate solution were added tothe residue and the solid precipitated was collected by filtration. Theobtained solid was purified by a silica gel column chromatography(silica gel: Wako Gel (C200), eluent: chloroform-methanol=10:1) toobtain8-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline(3.2 g).

m.p. 179.5–181.5° C.

(2) In a mixture of 1 M hydrochloric acid (30 mL) and tetrahydrofuran(15 mL),8-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline(3.2 g) was stirred at room temperature for 2 hours and then at 70° C.for 5.5 hours. The tetrahydrofuran was distilled off under reducedpressure, and the residue was made basic with a 41% aqueous sodiumhydroxide solution under ice-cooling and extracted three times withethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, after which the desiccating agent was filtered off andthe filtrate was concentrated under reduced pressure.

The resultant residue was dissolved in ethanol (12.5 mL)-chloroform (6mL), and potassium cyanide (5.4 g) was added thereto. To the mixturethus obtained was added acetic acid (4.4 mL) under ice-cooling over aperiod of 10 minutes, and the resulting mixture was stirred at roomtemperature for 6 hours. The reaction mixture was separated with ethylacetate and a saturated aqueous sodium hydrogencarbonate solution andthe organic layer was dried over anhydrous sodium sulfate, after whichthe desiccating agent was filtered off and the filtrate was concentratedunder reduced pressure.

The resultant residue was dissolved in pyridine (15 mL), and phosphorusoxychloride (7.5 mL) was added thereto under ice-cooling. The reactionmixture was stirred at room temperature for 24 hours and then carefullypoured into ice water. The reaction mixture thus treated was extractedthree times with a mixed solvent of chloroform and methanol, and thecombined organic layer was dried over anhydrous sodium sulfate, afterwhich the desiccating agent was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by asilica gel column chromatography (silica gel: Wako Gel (C200), eluent:hexane-ethyl acetate=5:1) and then crystallized from diisopropyl etherto obtain8-(2,4-dichlorophenyl)-2-methyl-4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)quinoline(1.0 g).

m.p. 177.5–179.5° C.

(3) In 96% formic acid (5 mL) was dissolved8-(2,4-dichlorophenyl)-2-methyl-4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)quinoline(1.0 g), and hydrogen chloride gas was bubbled into the solution underice-cooling to saturate the solution therewith. The reaction mixture wasstirred at room temperature for 4 hours and then distilled under reducedpressure to remove the solvent. The residue was separated withchloroform and a saturated aqueous sodium hydrogen-carbonate solution,and the organic layer was dried over anhydrous sodium sulfate. Thedesiccating agent was filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by a silica gel columnchromatography (silica gel: Wako Gel (C200), eluent:chloroform-methanol=10:1) and then recrystallized from tetrahydrofuranto obtain the title compound (174 mg).

m.p. 263.5–265.5° C.

Table 1 and Table 14 list the compound obtained in Example 3 and acompound obtained by the same procedure as in Example 3.

EXAMPLE 4 Synthesis of4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-1-(2,4-dichlorophenyl)-2,3,6,-trimethyl-1H-pyrrolo[2,3-b]pyridine(compound 12-01)

(1) After 60% sodium hydride (an oil dispersion) (0.97 g) was washedwith hexane and then suspended in N,N-dimethylformamide (10 mL), asolution of1-(2,4-dichlorophenyl)-4-hydroxy-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(6.50 g) in N,N-dimethyl-formamide (90 mL) was added dropwise thereto.The resulting mixture was stirred at 40° C. for 30 minutes, after whichN-phenylbis(trifluoromethanesulfonimide) (8.65 g) was added thereto allat once, followed by stirring at room temperature for 30 minutes. To thesolution thus obtained was added 4-piperidone ethylene ketal (16.4 g),and the reaction was carried out at 90° C. for 2 hours, at 100° C. for1.5 hours, and then at 120° C. for 2.5 hours. After the reaction mixturewas cooled to room temperature, a saturated aqueous ammonium chloridesolution was poured thereinto, followed by extraction with ethylacetate, and the organic layer was dried over anhydrous sodium sulfate.The desiccating agent was filtered off, after which the filtrate wasconcentrated under reduced pressure, and the residue was purified by asilica gel column chromatography (silica gel: Wako Gel (C200), eluent:hexane-ethyl acetate=3:1) to obtain1-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azapiro[4.5]dec-8-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(5.23 g).

(2) After1-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]-pyridine(5.21g) was stirred in a mixture of 4 M hydrochloric acid (60 mL) andtetrahydrofuran (60 mL) at room temperature for 2.5 hours, 6 Mhydrochloric acid (30 mL) was added thereto and the resulting mixturewas stirred overnight. After completion of the reaction, the reactionmixture was poured into a saturated aqueous sodium hydrogencarbonatesolution and extracted three times with ethyl acetate. The combinedorganic layer was dried over anhydrous sodium sulfate, after which thedesiccating agent was filtered off and the filtrate was concentratedunder reduced pressure. The crystals thus obtained were washed withethyl acetate to obtain1-(2,4-dichloropheny1)-4-(4-oxopiperidin-1-yl)-2,3,6-trimethy1-1H-pyrrolo[2,3-b]pyridine(3.83 g).

(3) In ethanol (10 mL)-chloroform (4 mL) was dissolved1-(2,4-dichlorophenyl)-4-(4-oxopiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(0.55 g), and potassium cyanide (0.91 g) was added thereto. To theresulting mixture was added acetic acid (0.75 mL) under ice-cooling overa period of 15 minutes, followed by stirring at room temperature for 2hours. The reaction mixture was separated with ethyl acetate and asaturated aqueous sodium hydrogencarbonate solution and the organiclayer was dried over anhydrous sodium sulfate, after which thedesiccating agent was filtered off and the filtrate was concentratedunder reduced pressure.

The resultant residue was dissolved in pyridine (6.4 mL), and phosphorusoxychloride (1.3 mL) was added thereto under ice-cooling. The reactionmixture was stirred at room temperature for 1 hour and then at 60° C.for 1 hour. The reaction mixture was carefully poured into ice water andextracted three times with ethyl acetate, and the combined organic layerwas dried over anhydrous sodium sulfate, after which the desiccatingagent was filtered off and the filtrate was concentrated under reducedpressure. The residue was purified by a silica gel column chromatography(silica gel: Wako Gel (C200), eluent: hexane-ethyl acetate=4:1) toobtain4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)-1-(2,4-dichlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(0.33 g).

(4) In methylene chloride (2.0 mL) was dissolved4-(4-cyano-1,2,3,6-tetrahydropyridin-1-yl)-1-(2,4-dichlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(0.19 g), followed by adding thereto concentrated sulfuric acid (0.5 mL)under ice-cooling, and the resulting mixture was slowly heated to roomtemperature and then stirred overnight. The reaction mixture wasseparated with ethyl acetate and a saturated aqueous sodiumhydrogencarbonate solution, and the aqueous layer was extracted twicewith ethyl acetate. The combined organic layer was dried over anhydroussodium sulfate and the desiccating agent was filtered off, after whichthe filtrate was concentrated under reduced pressure. The residue waspurified by a silica gel column chromatography (silica gel: Wako Gel(C200), eluent: chloroform-methanol=30:1) and the crystals precipitatedwere washed with ethyl acetate to obtain the title compound (0.10 g).

m.p. 265.0–267.0° C.

Table 11 and Table 12 list the compound obtained in Example 4 andcompounds obtained by the same procedure as in Example 4.

EXAMPLE 5 Synthesis of4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-(2,4-dichlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(compound 12-09)

(1) After 60% sodium hydride (an oil dispersion) (79 mg) and a smallamount of 35% potassium hydride (an oil dispersion) were washed twicewith hexane, tetrahydrofuran (2.0 mL) and diethyl carbonate (0.21 g)were added thereto and the resulting mixture was heated at 80° C. Then,a solution of1-(2,4-dichlorophenyl)-4-(4-oxopiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(0.29 g) synthesized by the same procedure as in Example 4 intetrahydrofuran (2.0 mL) was added dropwise thereto over a period of 10minutes, and the resultant mixture was heated under reflux for 1.5hours. After the reaction mixture was cooled to room temperature, asaturated aqueous ammonium chloride solution was poured into thereaction mixture, which was then extracted three times with ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate. The desiccating agent was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by asilica gel column chromatography (silica gel: Wako Gel (C200), eluent:hexane-ethyl acetate=4:1) to obtain1-(2,4-dichlorophenyl)-4-(3-ethoxycarbonyl-4-oxopiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(0.14 g).

(2) In ethanol (3.0 mL) was dissolved1-(2,4-dichlorophenyl)-4-(3-ethoxycarbonyl-4-oxopiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(0.13 g), and the solution was cooled to −15° C. Then, sodium borohydride (26 mg) was added thereto and the resulting mixture was stirredovernight while being slowly heated to 0° C. A saturated aqueousammonium chloride solution was poured into the reaction mixture, whichwas then extracted three times with ethyl acetate. The combined organiclayer was dried over anhydrous sodium sulfate. The desiccating agent wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was purified by a silica gel column chromatography (silicagel: Wako Gel (C200), eluent: chloroform-methanol=50:1) to obtain1-(2,4-dichlorophenyl)-4-(3-ethoxycarbonyl-4-hydroxy-piperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(35 mg).

(3) In methylene chloride (1.5 mL) were dissolved1-(2,4-dichlorophenyl)-4-(3-ethoxycarbonyl-4-hydroxypiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(53 mg), triethylamine (34 mg) and a small amount of4-dimethylaminopyridine. Methanesulfonyl chloride (25 mg) was addedthereto and the resulting mixture was stirred at room temperature for 2hours. A saturated aqueous sodium hydrogencarbonate solution was pouredinto the reaction mixture, which was then extracted three times withchloroform. The combined organic layer was dried over anhydrous sodiumsulfate. The desiccating agent was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inbenzene (1.0 mL), followed by adding thereto1,8-diazabicyclo[5.4.0]-7-undecene (17 mg), and the resulting mixturewas heated under reflux for 1 hour. A saturated aqueous ammoniumchloride solution was poured into the reaction mixture, which was thenextracted three times with ethyl acetate. The combined organic layer wasdried over anhydrous sodium sulfate, after which the desiccating agentwas filtered off and the filtrate was concentrated under reducedpressure. The residue was purified by a silica gel column chromatography(silica gel: Wako Gel (C200), eluent: hexane-ethyl acetate=5:1) toobtain4-(5-ethoxy-carbonyl-1,2,3,6-tetrahydropyridin-1-yl)-1-(2,4-dichlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(27 mg).

(4) In ethanol (1.0 mL) was dissolved4-(5-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl)-1-(2,4-dichlorophenyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine(27 mg), followed by adding thereto a 1 M aqueous sodium hydroxidesolution (1.0 mL), and the resulting mixture was stirred at roomtemperature for 8.5 hours. A saturated aqueous ammonium chloridesolution was poured into the reaction mixture, which was then extractedthree times with chloroform. The combined organic layer was dried overanhydrous sodium sulfate. The desiccating agent was filtered off and thefiltrate was concentrated under reduced pressure.

The resultant residue was suspended in a mixed solvent ofN,N-dimethylformamide (0.8 mL) and chloroform (0.2 ml), and1-hydroxybenzotriazole monohydrate (18 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 mg) wereadded thereto. After the resulting mixture was stirred at roomtemperature for 40 minutes, a few drops of 28% aqueous ammonia solutionwas added thereto, and the mixture thus obtained was stirred at roomtemperature for 1.5 hours. A saturated aqueous sodium hydrogencarbonatesolution was poured into the reaction mixture, which was then extractedthree times with ethyl acetate. The combined organic layer was driedover anhydrous sodium sulfate. The desiccating agent was filtered offand the filtrate was concentrated under reduced pressure. The residuewas purified by a silica gel column chromatography (silica gel: Wako Gel(C200), eluent: hexane-ethyl acetate=1:2) and crystallized from a mixedsolvent of diisopropyl ether and ethyl acetate to obtain the titlecompound (6.0 mg).

Table 12 lists the compound obtained in Example 5.

EXAMPLE 6 Synthesis of5-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-(N-ethyl-2,4-dichloroanilino)-4-methylthiazole(compound 15-01)

(1) After 2-(N-ethyl-2,4-dichloroanilino)-4-methylthiazole hydrochloride(6.0 g) and calcium carbonate (4.6 g) were suspended in a mixed solventof chloroform (90 mL) and methanol (36 mL), benzyltrimethylammoniumtribromide (7.2 g) was added thereto in small portions. The solids inthe reaction mixture were filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by a silica gel columnchromatography (silica gel: Wako Gel (C200), eluent: hexane-ethylacetate=9:1) to obtain5-bromo-2-(N-ethyl-2,4-dichloroanilino)-4-methylthiazole (4.5 g).

(2) A mixture of5-bromo-2-(N-ethyl-2,4-dichloroanilino)-4-methylthiazole (0.20 g),5-carbamoyl-1,2,3,6-tetrahydropyridin hydrochloride (178 mg), sodiumhydrogencarbonate (94 mg) and ethanol (1.5 mL) was allowed to react in asealed tube at 120° C. for 3 days. The reaction mixture was separatedwith water and chloroform and the aqueous layer was extracted withchloroform, after which the combined organic layer was dried overanhydrous sodium sulfate. The desiccating agent was filtered off and thefiltrate was concentrated under reduced pressure. The residue waspurified by a silica gel column chromatography (silica gel: Wako Gel(C200), eluent: chloroform-methanol=20:1) and then crystallized fromdiisopropyl ether to obtain the title compound (34 mg).

m.p. 148.0–150.0° C.

Table 15 lists the compound obtained in Example 6.

EXAMPLE 7 Synthesis of2-{l-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-piperidin-4-ylidene}-acetamide(compound 1-22) and2-{1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridin-4-yl}-acetamide(compound 1-05)

(1) In a mixture of 1 M hydrochloric acid (26 mL) and tetrahydrofuran(13 mL), 8-(2,4-dichloro-phenyl)-4(1,4dioxa-8-azapiro[4.5]dec-8-yl)-2-methylquinoline (2.6 g) obtained bythe same procedure as in Example 3, (1) was stirred at room temperaturefor 2 hours and then at 70° C. for 5.5 hours. The tetrahydrofuran wasdistilled off under reduced pressure, and the residue was made basicwith a 41% aqueous sodium hydroxide solution under ice-cooling andextracted three times with ethyl acetate. The combined organic layer wasdried over anhydrous sodium sulfate, after which the desiccating agentwas filtered off and the filtrate was concentrated under reducedpressure.

The resultant residue was dissolved in tetrahydrofuran (10 mL) and theresulting solution was added dropwise to a solution of Horner-Emmonsreagent that had previously been prepared from ethyldiethylphosphonoacrtate (2.05 g) and 60% sodium hydride (an oildispersion) (293 mg) in tetrahydrofuran (10 mL), under ice-cooling overa period of 20 minutes. The ice bath was removed, and the reactionmixture was stirred at room temperature for 30 minutes, quenched with asaturated aqueous ammonium chloride solution, and then extracted twicewith ethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, after which the desiccating agent was filtered off andthe filtrate was concentrated under reduced pressure. The resultantresidue was purified by a silica gel column chromatography (silica gel:Wako Gel (C200), eluent: hexane-ethyl acetate=9:1) and then crystallizedfrom diisopropyl ether to obtain8-(2,4-dichlorophenyl)-2-methyl-4-(4-ethoxycarbonyl-methylidenepiperidin-1-yl)quinoline(2.4 g).

(2) In a mixed solvent of 85% potassium hydroxide (1.3 g) and water (1.4mL)-ethanol (8 mL),8-(2,4-dichlorophenyl)-2-methyl-4-(4-ethoxycarbonyl-methylidenepiperidin-1-yl)quinoline(2.3 g) was stirred at 80° C. for 1 hour. The reaction mixture wasneutralized with 3 M hydrochloric acid under ice-cooling and stirredunder ice-cooling for 2 hours and then at room temperature for 30minutes. The solid precipitated was collected by filtration to obtain amixture (1.5 g) of2-{1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-piperidin-4-ylidene}aceticacid and2-{1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridin-4-yl}aceticacid.

(3) A mixture (400 mg) of2-{1-[8-(2,4-dichlorophenyl)-2methylquinolin-4-yl]-piperidin-4-ylidene}aceticacid and 2-{1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridin-4-yl}acetic acid, 1-hydroxybenzotriazolemonohydrate (215 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (215 mg) were stirred in N,N-dimethyl-formamide (2 mL) atroom temperature for 20 minutes. Then, a 28% aqueous ammonia solution(0.075 mL) was added thereto and the resulting mixture was stirred atroom temperature for 3 days. The reaction mixture was separated withchloroform and water, and the organic layer was dried over anhydroussodium sulfate. The desiccating agent was filtered off and the filtratewas concentrated under reduced pressure. The residue was separated andpurified twice by a silica gel column chromatography (silica gel: WakoGel (C200), eluent: chloroform-ethanol=50:1), after which the purifiedproducts were crystallized from diethyl ether and diisopropyl ether,respectively, to obtain the title compound 1-22 (109 mg) and the titlecompound 1-05 (43 mg), respectively.

Compound 1-22: m.p. 225.0–227.0° C.

Compound 1-05: m.p. 160.0–162.0° C.

Table 1 and Table 16 list the compounds obtained in Example 7 andcompounds obtained by the same procedure as in Example 7.

EXAMPLE 8 Synthesis of8-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline

(1) After having been washed with hexane, 60% sodium hydride (an oildispersion) (1.68 g) was suspended in N,N-dimethylformamide (20 mL). Tothe resulting suspension was added a suspension of8-bromo-4-hydroxy-2-methylquinoline (10.0 g) in N,N-dimethylformamide(35 mL) at room temperature over a period of 10 minutes, followed bystirring at room temperature for 30 minutes. To the resultant solutionwas added N-phenylbis(trifluoromethanesulfonimide) (15.0 g) all at once,followed by stirring at room temperature for 1 hour.

To the resultant reaction mixture was added 4-piperidone ethylene ketal(11.0 g), and the resulting mixture was stirred at room temperature for24 hours and heated under reflux at 60° C. for 4 hours and then for 2.5hours. After 4-piperidone ethylene ketal (5.5 g) was added thereto, themixture thus obtained was heated under reflux for 3 hours. The reactionmixture was cooled to room temperature, poured into water (200 ml) andthen stirred for 24 hours. The solid precipitated was collected byfiltration and purified by a silica gel column chromatography (silicagel: Wako Gel (C200), eluent: hexane-ethyl acetate=5:1 to 3:1) to obtain8-bromo-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline (10.3g), m.p. 156.0–158.0° C.

(2) Under a nitrogen atmosphere, 8-bromo-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline (10.2 g), 2,4-dichlorophenylboric acid(6.0 g) and sodium carbonate (8.93 g) were suspended in a mixed solventof deaerated water (24 mL), toluene (12 mL) and ethanol (12 mL),followed by adding thereto tetrakis-(triphenylphosphine) palladium (1.6g), and the resulting mixture was heated under reflux for 16 hours. Thereaction mixture was cooled to room temperature and separated with ethylacetate and a saturated aqueous ammonium chloride solution. After theaqueous phase was extracted with ethyl acetate, the combined organicphase was dried over anhydrous sodium sulfate. The desiccating agent wasfiltered off, after which the filtrate was concentrated under reducedpressure and the resultant residue was crystallized from diisopropylether. The crystals were collected by filtration and washed with a smallamount of diisopropyl ether to obtain the title compound (10.5 g).

m.p. 179.5–181.5° C.

EXAMPLE 9 Synthesis of8-(2,4-dichlorophenyl)-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methyl-quinoline(compound 1-01)

(1) After having been washed with hexane, 60% sodium hydride (an oildispersion) (1.0 g) was suspended in N-methylpyrrolidone (40 mL). To thesuspension was added 8-bromo-4-hydroxy-2-methylquinoline (5.0 g) all atonce at room temperature, followed by stirring at room temperature for 1hour. To the resulting solution was addedN-phenylbis-(trifluoromethanesulfonimide) (15.0 g) all at once, followedby stirring at room temperature for 1 hour.

To the resultant reaction mixture were added sodium hydrogencarbonate(5.3 g) and 4-carbamoyl-1,2,3,6-tetrahydropyridine hydrochloride (6.8g), and the resulting mixture was stirred at 130° C. for 30 minutes.After this reaction mixture was cooled to room temperature, water (100mL) was added thereto, followed by stirring at room temperature for 2hours. The solid precipitated was collected by filtration and thenwashed with water to obtain8-bromo-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methyl-quinoline(4.8 g).

m.p. 225.0–227.0° C.

(2) Under a nitrogen atmosphere,8-bromo-2-methyl-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)quinoline(4.7 g), 2,4-dichlorophenylboric acid (2.9 g) and sodium carbonate (4.5g) were suspended in a mixed solvent of deaerated water (14 mL), toluene(7 mL) and ethanol (7 mL), followed by adding theretotetrakis(triphenylphosphine)palladium (0.81 g), and the resultingmixture was heated under reflux for 5 hours. The reaction mixture wascooled to room temperature and stirred at room temperature for 3 hours.The solid precipitated was collected by filtration and washed with awater-ethanol (2:1) mixed solvent (30 mL) and then ethanol (30 mL) toobtain the title compound (4.7 g).

Table 1 lists the compound obtained in Example 9.

EXAMPLE 10 Synthesis of8-(2,4-dichlorophenyl)-4-(4-isopropyloxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline(compound 1-14)

(1) After having been washed with hexane, 60% sodium hydride (an oildispersion) (1.0 g) was suspended in N-methylpyrrolidone (30 mL). To thesuspension was added 8-bromo-4-hydroxy-2-methylquinoline (5.0 g) all atonce at room temperature, followed by stirring at room temperature for 1hour. To the resulting solution was addedN-phenylbis-trifluoromethanesulfonimide) (9.0 g) all at once, followedby stirring at room temperature for 1 hour.

To the resultant reaction mixture was added4-isopropyloxycarbonyl-1,2,3,6-tetrahydropyridine (8.5 g), and theresulting mixture was stirred overnight at room temperature. Thisreaction mixture was poured into a mixture of water and ethyl acetate tobe separated. After the aqueous phase was extracted with ethyl acetate,the combined organic phase was dried over anhydrous sodium sulfate. Thedesiccating agent was filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by a silica gel columnchromatography (silica gel: Wako Gel (C200), eluent: hexane-ethylacetate=9:1), and the solid thus obtained was washed with a mixture ofdiisopropyl ether and hexane to obtain8-bromo-4-(4-isopropyloxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline(6.0 g).

m.p. 130.0–131.0° C.

(2) Under a nitrogen atmosphere,8-bromo-4-(4-isopropyloxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline(5.9 g), 2,4-dichlorophenylboric acid (3.2 g) and sodium carbonate (4.8g) were suspended in a mixed solvent of deaerated water (15 mL), toluene(7.5 mL) and ethanol (7.5 mL), followed by adding theretotetrakis(triphenylphosphine)palladium (0.88 g), and the resultingmixture was heated under reflux for 5 hours. The reaction mixture wascooled to room temperature to be separated. After the aqueous phase wasextracted with ethyl acetate, the combined organic phase was dried overanhydrous sodium sulfate. The desiccating agent was filtered off, afterwhich the filtrate was concentrated under reduced pressure and theresultant residue was crystallized from diisopropyl ether. The crystalswere collected by filtration and washed with a small amount ofdiisopropyl ether to obtain the title compound (5.3 g).

m.p. 131.0–133.0° C.

Table 1 lists the compound obtained in Example 10.

EXAMPLE 11 Synthesis of8-(2,4-dichlorophenyl)-4-(4-carboxy-1,2,3,6-tetrahydropyridin-2-methyl-quinoline(compound 1-11)

In concentrated hydrochloric acid (10 mL) was suspended8-(2,4-dichlorophenyl)-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline(0.10 g), and the suspension was heated under reflux for 1 hour. Afterthe reaction mixture was concentrated under reduced pressure, 28%aqueous ammonia (2 mL) was added thereto, followed by concentrationunder reduced pressure. The residue was purified by a silica gel columnchromatography (silica gel: Wako Gel (C200), eluent:chloroform-methanol=20:1 to 10:1), and the solid precipitated was washedwith ethyl acetate to obtain the title compound (74 mg).

m.p. 218.0–220.0° C.

Table 1 lists the compound obtained in Example 11.

TABLE 1^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁵ R⁶ R⁷ Arcrystallization) 1-01 1, 3, 9

CH CH₃ H H H

263.5–265.5(MeOH) 1-02 2

CH CH₃ H H H

220.5–222.5(AcOEt) 1-03 2

CH CH₃ H H H

242.0–244.0(MeOH) 1-04 2

N CH₃ H H H

220.0–222.0(Et₂O) 1-05 7

CH CH₃ H H H

160.0–162.0(IPE) 1-06 1

CH CH₃ H H H

235.0–236.0(MeOH) 1-07 1

CH CH₃ H H H

215.0–216.0(MeOH) 1-08 1

CH CH₃ H H H

228.0–230.0(MeOH) 1-09 1

CH CH₃ H Cl H

256.0–258.0(MeOH) 1-10 1

CH CH₃ H CH₃ H

252.0–254.0(MeOH) 1-11 11

CH CH₃ H H H

218.0–220.0(AcOEt) 1-12 1

CH CH₃ H F H

273.0–275.0(MeOH) 1-13 1

CH CH₃ H OCF₃ H

235.0–236.0(MeOH) 1-14 10

CH CH₃ H H H

131.0–133.0(IPE/hexane) 1-15 2

CH CH₃ H H H

230.0–232.0(AcOEt) 1-16 2

CH CH₃ H H H

144.5–146.5(AcOEt) 1-17 2

CH CH₃ H H H

140.5–142.5(Et₂O) 1-18 2

CH CH₃ H H H

185.0–187.0(EtOH) 1-19 2

N CH₃ H H H

Amorphous^(*2) 1-20 1

CH CH₃ H F H

237.0–238.0(MeOH) 1-21 1

CH CH₃ H OCF₃ H

170.0–173.0(EtOH)^(*3) 1-22 7

CH CH₃ H H H

225.0–227.0(Et₂O) 1-23 1

CH CH₃ H N(CH₃)₂ H

202.0–204.0(EtOH) 1-24 1

CH CH₃ H N(CH₃)₂ H

187.0–189.0(IPA/AcOEt)^(*3) 1-25 1

CH CH₃ F H H

244.0–246.0(EtOH) 1-26 1

CH CH₃ F H H

214.0–216.0(EtOH) 1-27 1

CH H H H H

>235(decomposed)(EtOH) 1-28 1

CH H H H H

220.5–222.5(EtOH) 1-29 1

CH NH₂ H H H

>230(decomposed)(MeOH) 1-30 1

CH NH₂ H H H

155.0–158.5(IPA/Et₂O) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; MeOH = methanol, EtOH = ethanol,AcOEt = ethyl acetate, Et₂O = diethyl ether ^(*21)H NMR(200 MHz, CDCl₃);δ 2.41(3H, s), 2.48–2.66(2H, m), 3.72–3.95(2H, m), 4.34–4.46(2H, m),6.76–6.87(1H, m), 7.05(1H, br, s), 7.42(1H, d, J=8.4 Hz), 7.47–7.63(3H,m), 7.68(1H, dd, J=1.3, 7.3 Hz), 7.72(1H, d, J=1.8 Hz), 8.04(1H, dd,J=1.3, 8.4 Hz). MS(ES, Pos); 435(M + Na)⁺, 437(M + Na + 2)⁺, 439(M +Na + 4)⁺ ^(*3)HCl salt

TABLE 2^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁵ R⁶ Arcrystallization) 2-01 2

N CH₃ H H

221.0–223.0(AcOEt) 2-02 1

CH CH₃ H H

277.0–279.0(AcOEt) 2-03 2

N CH₃ H H

100.0–102.0(IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, IPE =diisopropyl ether

TABLE 3^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁵ Arcrystallization) 3-01 2

CH CH₃ CH₃

245.0–247.0(AcOEt/IPE) 3-02 2

N CH₃ CH₃

245.0–247.0(AcOEt/IPE) 3-03 2

CH CH₃ CH₃

252.0–254.0(AcOEt) 3-04 2

N CH₃ CH₃

255.0–257.0(AcOEt) 3-05 2

CH CH₃ CH₃

187.0–189.0(AcOEt/IPE) 3-06 2

N CH₃ CH₃

145.0–147.0(EtOH/AcOEt)^(*2) 3-07 2

CH CH₃ CH₃

150.0–152.0(AcOEt) 3-08 2

N CH₃ CH₃

209.0–211.0(AcOEt) 3-09 2

CH CH₃ CH₃

245.0–247.0(AcOEt/IPE) 3-10 2

CH CH₃ CH₃

253.0–255.0(AcOEt/IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; EtOH = ethanol, AcOEt = ethylacetate, IPE = diisopropyl ether ^(*2)HCl salt

TABLE 4^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁵ R⁹ Arcrystallization) 4-01 2

N CH₃ H CH₃

Amorphous^(*2) 4-02 2

N CH₃ H CH₃

169.0–171.0(AcOEt/Et₂O) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, Et₂O =diethyl ether ^(*21)H NMR(200 MHz, CDCl₃); δ 2.57–2.75(2H, m), 2.67(3H,s), 3.55(2H, t, J=5.7 Hz), 4.01(3H, s), 4.08–4.18(2H, m), 6.70–6.82(1H,m), 7.35(1H, dd, J=2.1, 8.6 Hz), 7.49(1H, d, J=2.1 Hz), 7.70(1H, s),8.09(1H, d, J=8.6 Hz). MS(ES, Pos.); 416(M + 1)⁺, 418(M + 3)⁺

TABLE 5^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁹ Arcrystallization) 5-01 2

N CH₃ CH₃

267.0–269.0(AcOEt) 5-02 2

N CH₃ CH₃

165.0–167.0(AcOEt) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate

TABLE 6^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁹ Arcrystallization) 6-01 2

N CH₃ CH₃

221.0–223.0(Et₂O) 6-02 2

N CH₃ CH₃

209.0–211.0(Et₂O) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; Et₂O = diethyl ether

TABLE 7^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁹ Arcrystallization) 7-01 2

N CH₃ CH₃

266.0–268.0(AcOEt) 7-02 1

CH CH₃ CH₃

231.0–233.0(AcOEt) 7-03 2

N CH₃ CH₃

211.0–213.0(AcOEt) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, Et₂O =diethyl ether

TABLE 8^(*)1

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ Arcrystallization) 8-01 2

N CH₃

283.0–285.0(AcOEt) 8-02 2

N CH₃

186.0–188.0(AcOEt/IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, IPE =diisopropyl ether

TABLE 9^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ Arcrystallization) 9-01 2

N CH₃

191.0–193.0(AcOEt/IPE) 9-02 2

N CH₃

217.0–219.0(AcOEt) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, IPE =diisopropyl ether

TABLE 10^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁵ R⁶ Arcrystallization) 10-01 2

CH CH₃ H H

242.0–244.0(Et₂O) 10-02 2

CH CH₃ H H

208.0–210.O(AcOEt/IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, Et₂O =diethyl ether, IPE = diisopropyl ether

TABLE 11^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁴ R⁵ Arcrystallization) 11-01 2

N CH₃ H

220.0–222.0(THF/hexane) 11-02 4

CH CH₃ H

238.0–240.0(CHCl₃/MeOH) 11-03 2

N CH₃ H

216.0–218.0(THF/hexane) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; MeOH = methanol, THF =tetrahydrofuran

TABLE 12^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A R⁴ R⁵ R⁶ Arcrystallization) 12-01 4

CH₃ CH₃ CH₃

265.0–267.0(AcOEt) 12-02 4

CH₃ CH₃ CH₃

273.0–275.0(AcOEt) 12-03 4

CH₃ CH₃ CH₃

267.0–269.0(AcOEt) 12-04 4

CH₃ CH₃ CH₃

208.0–210.0(AcOEt) 12-05 4

CH₃ CH₃ CH₃

170.0–172.0(AcOEt/IPE) 12-06 4

CH₃ CH₃ CH₃

162.0–164.0(AcOEt) 12-07 4

CH₃ CH₃ CH₃

249.0–251.0(AcOEt) 12-08 4

CH₃ CH₃ CH₃

203.0–205.0(CHCl₃/IPE) 12-09 5

CH₃ CH₃ CH₃

Amorphous^(*2) ^(*1)Com.No. = compound number, Ex.No. = example number,solvent for crystallization; AcOEt = ethyl acetate, IPE = diisopropylether ^(*21)H NMR(200 MHz, CDCl3); δ 2.06(3H, s), 2.40(3H, s), 2.45(3H,br. s), 2.48–2.60(2H, m), 3.21–3.43(2H, m), 3.86–3.96(2H, m), 6.54(1H,s), 6.70–6.77(1H, m), 7.29(1H, d, J=8.5 Hz), 7.39(1H, dd, J=2.3, 8.5Hz), 7.57(1H, d, J=2.3 Hz). MS(ES, Pos); 429(M + 1)⁺, 431(M + 3)⁺

TABLE 13^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A E R⁵ R⁶ R⁷ R⁸ Arcrystallization) 13-01 2

N H H H H

294.0–296.0(THF/CHCl₃) 13-02 2

N H H H H

133.0–135.0(AcOEt/IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, IPE =diisopropyl ether, THF = tetrahydrofuran

TABLE 14^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A R⁴ R⁵ R⁹ Arcrystallization) 14-01 3

CH₃ CH₃ H

241.0–243.0(AcOEt/IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, IPE =diisopropyl ether

TABLE 15^(*1)

Melting point (° C.) (solvent for Com.No. Ex.No. A R⁴ R⁹ Arcrystallization) 15-01 6

CH₃ CH₂CH₃

148.0–150.0(IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; IPE = diisopropyl ether

TABLE 16^(*1)

Melting point (° C.) (solvent Com.No. Ex.No. A E R⁴ R⁹ Ar forcrystallization) 16-01 2

CH CH₃ CH₂CH₃

100.0–102.0(Et₂O/hexane) 16-02 2

CH CH₃ CH₂CH₃

211.0–213.0(Et2O) 16-03 2

CH CH₃ CH₂CH₃

140.0–142.0(AcOEt) 16-04 2

CH CH₃ CH₂CH₃

138.0–140.0(Et₂O/hexane) 16-05 7

CH CH₃ CH₂CH₃

oilz^(*2) 16-06 7

CH CH₃ CH₂CH₃

oil^(*3) 16-07 7

CH CH₃

oil^(*4) 16-08 7

CH CH₃

oil^(*5) 16-09 7

CH CH₃

oil^(*6) 16-10 7

CH CH₃ CH₂CH₃

oil^(*7) 16-11 7

CH CH₃ CH₂CH₃

oil^(*8) 16-12 7

CH CH₃ CH₂CH₃

oil^(*9) 16-13 7

CH CH₃ CH₂CH₃

oil^(*10) 16-14 7

CH CH₃ CH₂CH₃

oil^(*11) 16-15 7

CH CH₃ CH₂CH₃

oil^(*12) 16-16 7

CH CH₃ CH₂CH₃

oil^(*13) 16-17 7

CH CH₃ CH₂CH₃

oil^(*14) 16-18 7

CH CH₃ CH₂CH₃

oil^(*15) 16-19 2

N CH₃ CH₂CH₃

117.0–119.0(IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, Et₂O =diethyl ether, IPE = diisopropyl ether ^(*21)H NMR (200 MHz, CDCl₃); δ1.20(3H, t, J=7.0 Hz), 1.29(6H, d, J=6.8 Hz), 2.12–2.34(2H, m), 2.20(3H,s), 2.36(3H, s), 2.80–3.04(3H, m), 3.30–4.39(6H, m), 3.69(3H, s),5.70(1H, s), 5.81(1H, s), 6.95–7.18(3H, m). MS(ES, Pos); 455(M + 1)⁺^(*31)H NMR (200 MHz, CDCl₃); δ 1.02–1.38(12H, m), 2.03–2.43(2H, m),2.21(3H, s), 2.37(3H, s), 2.72–3.08(3H, m), 3.17–4.35(6H, m), 4.15(2H,q, J=7.0 Hz), 5.69(1H, s), 5.81(1H, s), 6.94–7.17(3H, m). MS(ES, Pos);469(M + 1)⁺ ^(*41)H NMR (200 MHz, CDCl₃); δ 0.03–0.48(4H, m),1.04–1.39(10H, m), 2.08–2.34(2H, m), 2.19(3H, s), 2.33(3H, s),2.80–3.07(3H, m), 3.15–3.74(5H, m), 4.02–4.33(1H, m), 4.15(2H, q, J=7.0Hz), 5.69(1H, s), 5.80(1H, s), 6.96–7.22(3H, m). MS(SIMS, Pos); 495(M +1)⁺ ^(*51)H NMR (200 MHz, CDCl₃); δ 1.20–1.35(9H, m), 2.10–2.33(2H, m),2.19(3H, s), 2.36(3H, s), 2.78–3.06(3H, m), 3.30–3.74(4H, m),3.90–4.30(1H, m), 4.15(2H, q, J=7.0 Hz), 4.65–5.20(3H, m), 5.70(1H, s),5.82(1H, s), 5.92–6.20(1H, m), 6.94–7.17(3H, m). MS(SIMS, Pos); 481(M +1)⁺ ^(*61)H NMR (200 MHz, CDCl₃); δ 1.19–1.36(9H, m), 2.08–2.38(3H, m),2.22(3H, s), 2.38(3H, s), 2.80–3.05(3H, m), 3.35–3.77(4H, m),4.00–4.30(1H, m), 4.16(2H, q, J=7.0 Hz), 5.00–5.37(1H, m), 5.71(1H, s),5.87(1H, s), 6.98–7.33(3H, m). MS(SIMS, Pos); 479(M + 1)⁺ ^(*71)H NMR(200 MHz, CDCl₃); δ 1.13–1.38(12H, m), 1.87(3H, s), 2.18(3H, s),2.26–2.77(4H, m), 2.36(3H, s), 2.95(1H, sept, J=7.0 Hz), 3.33–4.32(6H,m), 4.19(2H, q, J=7.0 Hz), 5.74(1H, s), 6.96–7.17(3H, m). MS(ES, Pos);483(M + 1)⁺ ^(*81)H NMR (200 MHz, CDCl₃); δ 1.21(3H, t, J=7.0 Hz),1.28(6H, d, J=7.0 Hz), 2.04–2.41(2H, m), 2.21(3H, s), 2.36(3H, s),2.80–3.06(3H, m), 3.23–4.39(6H, m), 5.60(1H, s), 5.81(1H, s), 6.01(1Hbr. s), 6.93–7.15(3H, m). MS(FAB, Pos); 441(M + 1)⁺ ^(*91)H NMR (200MHz, CDCl₃); δ 1.21(3H, t, J=7.0 Hz), 1.29(6H, d, J=7.0 Hz),2.10–2.35(2H, m), 2.23(3H, s), 2.37(3H, s), 2.41–2.59(2H, m), 2.94(1H,sept, J=7.0 Hz), 3.31–4.38(6H, m), 5.14(1H, s), 5.83(1H, s),6.98–7.18(3H, m). MS(ES, Pos); 422(M + 1)⁺ ^(*101)H NMR (200 MHz,CDCl₃); δ 1.20(3H, t, J=7.0 Hz), 1.27(6H, d, J=7.0 Hz), 2.00–2.32(2H,m), 2.19(3H, s), 2.35(3H, s), 2.80–3.05(3H, m), 3.36–4.38(6H, m),5.36–5.71(3H, m), 5.73(1H, s), 6.96–7.18(3H, m). MS(FAB, Pos); 440(M +1)⁺ ^(*111)H NMR (200 MHz, CDCl₃); δ 1.20(3H, t, J=7.0 Hz), 1.27(6H, d,J=7.0 Hz), 2.06–2.32(2H, m), 2.19(3H, s), 2.35(3H, s), 2.72–3.06(3H, m),2.81(3H, d, J=5.0 Hz), 3.23–4.35(6H, m), 5.35–5.60(1H, m), 5.55(1H, s),5.80(1H, s), 6.92–7.16(3H, m). MS(FAB, Pos); 454(M + 1)⁺ ^(*121)H HMR(200 MHz, CDCl₃); δ 1.20(3H, t, J=7.0 Hz), 1.26(6H, d, J=7.0 Hz),2.06–2.30(2H, m), 2.20(3H, s), 2.36(3H, s), 2.46–2.61(2H, m),2.80–3.10(1H, m), 2.97(3H, s), 3.01(3H, s), 3.31–4.39(6H, m), 5.80(1H,s), 6.94–7.17(3H, m). MS(FAB, Pos); 468(M + 1)⁺ ^(*13)HCl salt, ¹H NMR(200 MHz, CDCl₃); δ 1.03–1.53(9H, m), 1.60–4.88(14H, m), 2.41(3H, s),4.45(2H, d, J=5.0 Hz), 5.56–6.62(3H, m), 6.84–7.59(8H, m), 13.37(1H, brs). MS(FAB, Pos); 530(M + 1)⁺ ^(*141)H NMR (200 MHz, CDCl₃); δ 1.20(3H,t, J=7.0 Hz), 1.28(6H, d, J=7.0 Hz), 1.75–2.03(4H, m), 2.09–2.32(2H, s),2.20(3H, s), 2.35(3H, s), 2.70–2.90(2H, m), 2.95(1H, sept, J=7.0 Hz),3.33–4.33(10H, m), 5.81(1H, s), 5.83(1H, s), 6.96–7.15(3H, m). MS(FAB,Pos); 494(M + 1)⁺ ^(*151)H NMR (200 MHz, CDCl₃); δ 1.20(3H, t, J=7.0Hz), 1.27(6H, d, J=7.0 Hz), 2.10–2.30(2H, m), 2.20(3H, s), 2.36(3H, s),2.41–2.60(2H, m), 2.96(1H, sept, J=7.0 Hz), 3.27–4.40(14H, m), 5.81(1H,s), 6.95–7.16(3H, m). MS(FAB, Pos); 510(M + 1)⁺

TABLE 17^(*1)

Melting point (° C.) (solvent Com.No. Ex.No. A R⁴ R⁵ Ar forcrystallization) 17-01 1

CH₃ H

209.0–211.0(AcOEt/IPE) 17-02 1

CH₃ CH₂CH₃

202.0–204.0(AcOEt/IPE) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetate, IPE =diisopropyl ether

TABLE 18^(*1)

Melting point (° C.) (solvent Com.No. Ex.No. A R⁴ Ar forcrystallization) 18-01 1

CH₃

230.0–231.0(EtOH) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; EtOH = ethanol

TABLE 19^(*1)

Melting point (° C.) (solvent Com.No. Ex.No. A E R⁴ R⁵ Ar forcrystallization) 19-01 2

N CH₃ H

213.0–215.0(EtOH) ^(*1)Com..No. = compound number, Ex.No. = examplenumber, solvent for crystallization; EtOH = ethanol

TABLE 20^(*1)

Melting point (° C.) (solvent Com.No. Ex.No. A E R⁴ Ar forcrystallization) 20-01 2

N CH₃

247.0–249.0(AcOEt) 20-02 2

N CH₃

181.0–183.0(AcOEt) ^(*1)Com.No. = compound number, Ex.No. = examplenumber, solvent for crystallization; AcOEt = ethyl acetateTest Example [CRF Receptor Bonding Test]

Rat frontal cortex membranes or monkey amygdaloid body membranes wereused as a receptor preparation.

¹²⁵I-CRF was used as ¹²⁵I-labeled ligand.

Bonding reaction using the ¹²⁵I-labeled ligand was carried out by thefollowing method described in The Journal of Neuroscience, 7, 88 (1987).Preparation of a receptor membranes:

Rat frontal cortex or monkey amygdaloid body was homogenized in 50 mMTris-HCl buffer (pH 7.0) containing 10 mM MgCl₂ and 2 mM EDTA andcentrifuged at 48,000× g, and the precipitate was washed once withTris-HCl buffer. The washed precipitate was suspended in 50 mM Tris-HClbuffer (pH 7.0) containing 10 mM MgCl_(2, 2)mM EDTA, 0.1% bovine serumalbumin and 100 kallikrein units/ml aprotinin, to obtain a membranepreparation.

CRF Receptor Bonding Test:

The membrane preparation (0.3 mg protein/ml), ¹²⁵I-CRF (0.2 nM) and atest drug were reacted at 25° C. for 2 hours. After completion of thereaction, the reaction mixture was filtered by suction through a glassfilter (GF/C) treated with 0.3% polyethyleneimine, and the glass filterwas washed three times with phosphate-buffered saline containing 0.01%Triton X-100.After the washing, the radioactivity of the filter paperwas measured in a gamma counter.

The amount of ¹²⁵I-CRF bonded when the reaction was carried out in thepresence of 1 μM CRF was taken as the degree of nonspecific binding of¹²⁵I-CRF, and the difference between the total degree of ¹²⁵I-CRFbinding and the degree of nonspecific ¹²⁵I-CRF binding was taken as thedegree of specific ¹²⁵I-CRF binding. An inhibition curve was obtained byreacting a definite concentration (0.2 nM) of ¹²⁵I-CRF with variousconcentrations of each test drug under the conditions described above. Aconcentration of the test drug at which binding of ¹²⁵I-CRF is inhibitedby 50% (IC₅₀) was determined from the inhibition curve.

As a result, it was found that compounds 1-01, 1-02, 1-05, 1-06, 1-07,1-09, 1-10, 1-12, 1-15, 1-16, 12-01 to 12-09, 16-05, 16-06 and 16-12 canbe exemplified as typical compounds having an IC₅₀ value of 500 nM orless.

INDUSTRIAL APPLICABILITY

According to the present invention, compounds having a high affinity forCRF receptors have been provided. These compounds are effective againstdiseases in which CRF is considered to be involved, such as depression,anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea,eating disorder, hypertension, gastral diseases, drug dependence,epilepsy, cerebral infarction, cerebral ischemia, cerebral edema,cephalic external wound, inflammation, immunity-related diseases,alpecia, etc.

1. A tetrahydropyridino or piperidino heterocyclic derivativerepresented by the formula [I]:A-Het  [I] wherein A is a group represented by the following formula[II] or [III]:

wherein the position of substitution by the Y—(CH₂)_(n)-group of thegroup represented by the formula [II] is 4-position or 5-position, theposition of substitution by the Y—C(R⁰)═ group of the group representedby the formula [III] is 3-position or 4-position, R⁰ is a hydrogen atom,a C₁₋₅alkyl group, a C₃₋₈cycloalkyl group or a C₃₋₈cycloalkyl-C¹⁻⁵alkylgroup, n is an integer of 0 to 5, and Y is a cyano group, a grouprepresented by the formula —CONR¹(R²) (wherein each of R¹ and R², whichmay be the same or different, is a hydrogen atom, a C₁₋₅alkyl group, aC₃₋₈cycloalkyl group, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, aC₁₋₅alkoxy-C₁₋₅alkyl group, a C₃₋₈cycloalkyloxy-C₁₋₅alkyl group or aphenyl group, or R¹ and R², when taken together with the adjacentnitrogen atom, represent a 5- to 8-membered saturated heterocyclic grouprepresented by the formula:

(wherein B is CH₂, NH, N—C₁₋₅alkyl, N—C₃₋₈cycloalkyl,N—C₁₋₅alkyl-C₃₋₈cycloalkyl, O or S)) or a group represented by theformula —CO₂R³ (wherein R³ is a hydrogen atom, a C₁₋₅alkyl group, aC₃₋₈cycloalkyl group, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, aC₁₋₅alkoxy-C₁₋₅alkyl group, a C₃₋₈cycloalkyloxy-C₁₋₅alkyl group or aphenyl group), and Het is any of heterocyclic groups represented by thefollowing formulas to form (01) to form (02):

wherein E is CH or N, R⁴ is a hydrogen atom, a C₁₋₅alkyl group, aC₃₋₈cycloalkyl group, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, a hydroxylgroup, a C₁₋₅alkoxy group, a C₃₋₈cycloalkyloxy group, or a grouprepresented by the formula —N(R¹⁰)R¹¹ (wherein each of R¹⁰ and R¹¹,which may be the same or different, is a hydrogen atom, a C₁₋₅alkylgroup, a C₃₋₈cycloalkyl group or a C₃₋₈cycloalkyl-C₁₋₅alkyl group), eachof R⁵, R⁶ and R⁷, which may be the same or different, is a hydrogenatom, a halogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl group, aC₃₋₈cycloalkyl-C₁₋₅alkyl group, a hydroxyl group, a C₁₋₅alkoxy group, aC₃₋₈cycloalkyloxy group, a group represented by the formula—N(R^(12)R)¹³ (wherein each of R¹² and R¹³, which may be the same or different, isa hydrogen atom, a C₁₋₅alkyl group, a C₃₋₈cycloalkyl group or aC₃₋₈cycloalkyl-C₁₋₅alkyl group), a group represented by the formula—CO₂R¹⁴ (wherein R¹⁴ is a hydrogen atom, a C₁₋₅alkyl group, aC₃₋₈cycloalkyl group, a C₃₋₈cycloalkyl-C₁₋₅alkyl group, aC₁₋₅alkoxy-C₁₋₅alkyl group, a C₃₋₈cycloalkyloxy-C₁₋₅alkyl group or aphenyl group), a cyano group, a nitro group, a C₁₋₅alkylthio group, atrifluoromethyl group or a trifluoromethoxy group, and Ar is an aryl orheteroaryl group unsubstituted or substituted with 1 to 3 substituentswhich may be the same or different and are selected from halogen atoms,C₁₋₅alkyl groups, C₁₋₅alkoxy groups, C₁₋₅alkylthio groups,trifluoromethyl group, trifluoromethoxy group and groups represented bythe formula —N(R¹⁵)R¹⁶ (wherein each of R¹⁵ and R¹⁶, which may be thesame or different, is a hydrogen atom or a C₁₋₅alkyl group); or apharmaceutically acceptable salt thereof or its hydrate.
 2. Thetetrahydropyridino heterocyclic derivative, a pharmaceuticallyacceptable salt thereof or its hydrate according to claim 1, which is acompound represented by the formula [VI]:

wherein Het is as defined above, and m is 0 or
 1. 3. Thetetrahydropyridino heterocyclic derivative, a pharmaceuticallyacceptable salt thereof or its hydrate according to claim 2, which is acompound represented by the formula [V]:

wherein R⁴, R⁵, R⁶, R⁷, Ar and m are as defined above.
 4. Thetetrahydropyridino heterocyclic derivative or a pharmaceuticallyacceptable salt thereof or its hydrate according to claim 3, wherein min the formula [V] is
 0. 5. The tetrahydropyridino heterocyclicderivative, a pharmaceutically acceptable salt thereof or its hydrateaccording to claim 4, which is a compound represented by the formula[VI]:

wherein each of R¹⁸, R¹⁹ and R²⁰, which may be the same or different, isa hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, andeach of X⁵, X⁶ and X⁷, which may be the same or different, is a hydrogenatom, a methyl group, a chlorine atom, a trifluoromethyl group or atrifluoromethoxy group.
 6. The tetrahydropyridino heterocyclicderivative, a pharmaceutically acceptable salt thereof or its hydrateaccording to claim 5, which is a compound represented by the formula[VII]:

wherein R¹⁸, R¹⁹ and R²⁰ are as defined above, and each of X⁸ and X⁹,which may be the same or different, is a chlorine atom, atrifluoromethyl group or a trifluoromethoxy group.
 7. Thetetrahydropyridino heterocyclic derivative, a pharmaceuticallyacceptable salt thereof or its hydrate according to claim 6, which is acompound represented by the formula [VIII]:

wherein X⁹ is as defined above, and R²¹ is a hydrogen atom, a chlorineatom or a methyl group.
 8. A pharmaceutical composition, comprising atetrahydropyridino heterocyclic derivative, a pharmaceuticallyacceptable salt thereof or its hydrate according to any one of claims 1to 7, as an active ingredient, and a pharmaceutically acceptablecarrier.
 9. A method of treating depression or anxiety, said methodcomprising administering to a subject an effective amount of atetrahydropyridino heterocyclic derivative, a pharmaceuticallyacceptable salt thereof or its hydrate according to any one of claims 1to 7, as an antagonist against CRF receptors.
 10. The tetrahydropyridinoheterocyclic derivative, a pharmaceutically acceptable salt thereof orits hydrate according to claim 1, wherein Het is form (01).